The major enzymes involved in ethanol metabolism in mammalian liver are the alcohol dehydrogenases (ADHs) and the mitochondrial aldehyde dehydrogenase (ALDH2). ADHs oxidize ethanol into acetaldehyde and ALDH2 catalyzes the conversion of acetaldehyde to acetic acid. Both human ADH and ALDH have been reported to be polymorphic with alleles with different kinetic properties. It was proposed that the individual differences in the response to ethanol consumption may be genetically controlled. The most noted variant that influences alcohol metabolism is Glu487Lys, the "Oriental Variant" of ALDH2. The ALDH22 (Lys 487) allele has a relative high frequency among East Asian populations (30% to 50%) and has been extensively studied. The Glu 487 Lys substitution is due to a single nucleotide change (G to A) which resulted in an inactive enzyme under physiological conditions. Clinical studies also indicate that individuals who are either homozygous or heterozygous for the ALDH22 allele have altered acetaldehyde metabolism. Although it has been suggested that ALDH2 allele is a protective allele against the development of alcoholism, many questions remain unanswered. This is mainly due to the difficulty of dissecting the effects of altered A activity and other complicated variables such as the social, cultural and environmental influences on drinking behavior. In addition, the physiological consequences of altered acetaldehyde metabolism in human subjects are unclear. Moreover, it is difficult to obtain tissue samples from human subjects. Therefore, animal models with the same genetic background that can be studied under defined experimental conditions are needed to study the effects of reduced A activity on drinking behavior, the tissue damage resulting from ethanol consumption, and the natural role of ALDH2 under conditions when exogenous alcohol has not been administered. Currently, we have established two independent transgenic mice lines carrying the human ALDH2 (Lys487) allele. A genomic clone coding for the mouse ALDH2 gene was obtained. Two knock-out cassettes for the mouse ALDH2 gene were constructed. These are being introduced into embryonic stem cells to disrupt the mouse ALDH2 gene.